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Norihiro Nagai, Kanako Izumi-Nagai, Yuichi Oike, Takashi Koto, Shingo Satofuka, Yoko Ozawa, Kenji Yamashiro, Makoto Inoue, Kazuo Tsubota, Kazuo Umezawa, Susumu Ishida; Suppression of Diabetes-Induced Retinal Inflammation by Blocking the Angiotensin II Type 1 Receptor or Its Downstream Nuclear Factor-κB Pathway. Invest. Ophthalmol. Vis. Sci. 2007;48(9):4342-4350. doi: https://doi.org/10.1167/iovs.06-1473.
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purpose. To investigate the involvement of the renin-angiotensin system (RAS) and the nuclear factor (NF)-κB pathway with diabetes-induced retinal inflammation.
methods. Six weeks after induction of diabetes, C57BL/6 mice were treated with the angiotensin II type 1 receptor (AT1-R) blocker (ARB) telmisartan or valsartan, the AT2-R blocker PD123319, or the NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) daily for 1 week. Retinal mRNA and protein levels of the RAS components were examined by RT-PCR and Western blot, respectively. Leukocyte adhesion to the retinal vasculature was evaluated with a concanavalin A lectin perfusion-labeling technique. Retinal expression levels of intercellular adhesion molecule (ICAM)-1 and vascular endothelial growth factor (VEGF) were examined by RT-PCR and ELISA. ARB or DHMEQ was applied to murine capillary endothelial (b-End3) cells stimulated with a high concentration of glucose to analyze nuclear translocation of NF-κB via immunohistochemistry for p65 and mRNA and protein levels of ICAM-1 and monocyte chemotactic protein (MCP)-1.
results. Induction of diabetes led to a significant increase in retinal expression and production of the RAS components including angiotensin II, AT1-R, and AT2-R. Retinal adherent leukocytes were significantly suppressed by AT1-R, but not by AT2-R, blockade. Administration of the ARB, but not of PD123319, inhibited diabetes-induced retinal expression of ICAM-1 and VEGF. DHMEQ also suppressed these cellular and molecular inflammatory parameters in the diabetic retina to the levels obtained with ARB treatment. In vitro, glucose-induced nuclear translocation of NF-κB p65 and upregulation of ICAM-1 and MCP-1 were significantly suppressed by application of the ARB. The in vivo treatment with the ARB, as well as DHMEQ, attenuated the diabetes-induced retinal expression of angiotensin II and AT1-R, per se.
conclusions. The present data revealed significant a contribution of the AT1-R/NF-κB pathway to diabetes-induced retinal inflammation, providing a mechanistic reason for targeting AT1-R or NF-κB in the treatment of diabetic retinopathy.
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